Pharmaceutical combination

ABSTRACT

The present invention relates to a pharmaceutical combination for the treatment of schizophrenia and acute manic episodes associated with bipolar disorders, which comprises a compound which is active on a trace amine-associated receptor 1 (TAAR1 agonist) and an antipsychotic drug. This combination can reduce metabolic side effects which appear if using an antipsychotic drug alone.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a divisional of U.S. application Ser. No.13/189,600, Filed Jul. 25, 2011, which claims the benefit of EuropeanPatent Application No. 10171560.5, filed Aug. 2, 2010, which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Schizophrenia is a severe and chronic mental illness, with prevalenceestimates ranging from 1.4 to 4.6 per 1000 population.

Schizophrenic disorders and depression are caused by a combination ofgenetic and environmental factors, which include, for schizophrenia,probable neurodevelopmental abnormalities in gray and white matterstructures. Underlying the symptomatic phenomena in both diseases,disturbances in monoaminergic neurotransmission (e.g. serotonin,adrenaline, and noradrenaline) have been proposed.

These pathways are widely present in the CNS and, thus, are potentiallycapable of influencing many areas involved in emotional processing,cognition, and behavior. Until recently, the excess dopamine hypothesiswas the major pathophysiological theory of schizophrenia, based largelyon the effectiveness of D2 antagonists in controlling the acuteexacerbations of this disease.

Symptoms of schizophrenia, which typically emerge during adolescence orearly adulthood, are usually classified as positive, negative orcognitive. Positive symptoms include hallucinations, delusions andsevere thought disorganization. Negative symptoms are a group ofdeficits comprising flat affect, apathy, poverty of speech, anhedoniaand social withdrawal. Cognitive symptoms, such as deficits in attentionand working memory, are prominent features of the illness and have beenidentified as powerful predictors of social outcome.

Current atypical antipsychotics are efficacious primarily in themanagement of positive symptoms, yet have minimal effects on negativesymptoms and cognitive function, besides being associated withsignificant side-effects. Efficacy on cognitive symptoms and improvementof negative symptoms are the highest unmet need in schizophrenia.

First generation drugs are effective but associated with significantincidence of extrapyramidal symptoms, whereas second-generation(atypical) antipsychotics appear to have less incidence ofextrapyramidal side-effects and may be more effective in treatingcognition but increase the incidence and severity of metabolic syndrome.

A common antipsychotic drug for the treatment of schizophrenia isolanzapine. Olanzapine (Zyprexa) belongs to a drug class known asatypical antipsychotics. Other members of this class include clozapine(Clozaril), risperidone (Risperdal), aripiprazole (Abilify) andziprasidone (Geodon). Olanzapine binds to alpha-1, dopamine, histamine,muscarinic and serotonin type 2 (5-HT2) receptors.

Olanzapine is approved for the treatment of psychotic disorders, longterm treatment of bipolar disorders and in combination with fluoxetinefor the treatment of depressive episodes associated with bipolardisorders and for the treatment of resistant depression.

The treatment with antipsychotic drugs, such as olanzapine, may lead toserious side effects. The Food and Drug Administration requires allatypical antipsychotics to include a warning about the risk ofdeveloping hyperglycemia and diabetes, both of which are factors in themetabolic syndrome. These effects may be related to the drug's abilityto induce weight gain. Cardiometabolic adverse effects, such as weightgain, obesity, hypertension and lipid and glucose abnormalities, areparticularly problematic during development because they predict adultobesity, the metabolic syndrome, cardiovascular morbidity andmalignancy, especially if used in children and adolescents.

There may be an increased risk of increased blood sugar levels anddiabetes with olanzapine as well as the other antipsychotic medicationsin its class.

Many paediatric and adolescent patients who received second-generationantipsychotic medications experienced significant weight gain, alongwith varied adverse effects on cholesterol and triglyceride levels andother metabolic measures, according to a study in the October 28 issueof JAMA (JAMA, 2009 Oct. 28, 302 (16), 1765-73).

“Increasingly, the cardiometabolic effects of second-generationantipsychotic medications have raised concern. Cardiometabolic adverseeffects, such as age-inappropriate weight gain, obesity, hypertension,and lipid and glucose abnormalities, are particularly problematic duringdevelopment because they predict adult obesity, the metabolic syndrome,cardiovascular morbidity, and malignancy,” the authors wrote. Thecardiometabolic effects of these medications have not been sufficientlystudied in children and adolescent patients who have not previouslyreceived them, according to background information in the article.

Christoph U. Correll, M D, Zucker Hillside Hospital, North Shore-LongIsland Jewish Health System, Glen Oaks, and The Feinstein Institute forMedical Research, Manhasset, N.Y., and colleagues conducted a study ofweight and metabolic changes in a group of 272 paediatric patients (ages4 to 19 years) who had not previously received antipsychotic medication.Patients had mood spectrum (47.8%), schizophrenia spectrum (30.1%), anddisruptive or aggressive behaviour spectrum (22.1%) disorders. Fifteenpatients who refused participation or were nonadherent to medicationsserved as a comparison group. Patients were treated with theantipsychotic medications aripiprazole, olanzapine, quetiapine, orrisperidone for 12 weeks.

After a median of 10.8 weeks of treatment, weight increased by anaverage of 8.5 kg (18.7 lbs) with olanzapine (n=45), by 6.1 kg (13.4lbs) with quetiapine (n=36), by 5.3 kg (11.7 lbs) with risperidone(n=135), and by 4.4 kg (9.7 lbs) with aripiprazole (n=41) compared withminimal weight change of 0.2 kg (0.4 lbs) in the untreated comparisongroup (n=15). “Each antipsychotic medication was associated withsignificantly increased fat mass and waist circumference,” the authorswrote. “Altogether, 10% to 36% of patients transitioned to overweight orobese status within 11 weeks.”

The researchers also found that adverse changes during the study periodreached statistical significance for olanzapine and quetiapine for totalcholesterol, triglycerides, non-high-density lipoprotein (HDL)cholesterol, and ratio of triglycerides to HDL cholesterol. “Withrisperidone, levels of triglycerides increased significantly. Metabolicbaseline-to-endpoint changes were not significant with aripiprazole orin the untreated comparison group. Patients receiving quetiapine hadmodestly higher incidence rates of hyperglycaemia and the metabolicsyndrome and patients receiving olanzapine experienced the highestincidence rates.”

The authors noted that these results are concerning because they includefat mass and waist circumference, which are associated with themetabolic syndrome in adults treated with antipsychotic medications andheart disease in the general population. “Moreover, abnormal childhoodweight and metabolic status adversely affect adult cardiovascularoutcomes via continuation of these risk factors or independent oraccelerated mechanisms.”

“Our results, together with data from first-episode studies, suggestthat guidelines for antipsychotic medication exposure for vulnerablepaediatric and adolescent patients naïve to antipsychotic medicationshould consider more frequent [eg, biannual] cardiometabolic monitoringafter the first 3 months of treatment. Finally, in view of poor physicalhealth outcomes and suboptimal metabolic monitoring in the severelymentally ill, the benefits of second-generation antipsychoticmedications must be balanced against their cardiometabolic risks througha careful assessment of the indications for their use, consideration oflower-risk alternatives, and proactive adverse effect monitoring andmanagement,” the authors concluded.

In an accompanying editorial, Christopher K. Varley, MD, and JonMcClellan, MD, of Seattle Children's Hospital, Seattle, Wash., wrotethat these findings indicate there are other factors to considerregarding the use of atypical antipsychotic medications in children andadolescents.

“These medications can be lifesaving for youth with serious psychiatricillnesses such as schizophrenia, classically defined bipolar disorder,or severe aggression associated with autism. However, given the risk forweight gain and long-term risk for cardiovascular and metabolicproblems, the widespread and increasing use of atypical antipsychoticmedications in children and adolescents should be reconsidered.”

There is a need for new therapies with improved safety and tolerabilityprofile over current atypical antipsychotics. For example, newtreatments should not be associated with such side effects or adversereactions as described above.

Metabolic syndrome is a combination of medical disorders that increasethe risk of developing diabetes and cardiovascular disease. Risk factorsinclude for example abdominal obesity (excessive fat tissue in andaround the abdomen), blood fat disorders, elevated blood pressure,insulin resistance or glucose intolerance.

Trace amines (p-tyramine, β-phenylethylamine (PEA), octopamine, andtryptamine) are present throughout the CNS, closely paralleling themonoaminergic pathways, and at endogenous levels much lower than theseneurotransmitters. Their scarcity is due, in part, to their highturnover rate being good substrates for MAO A/B. Trace amines arestructurally related to, co-localized, and released with classicalbiogenic amine neurotransmitters. They are suggested to beneuromodulators of classical neurotransmitters like dopamine, serotoninand noradrenaline whose levels are the target of all knownantidepressants and most antipsychotics currently on the market or inclinics. Abnormalities in trace amine physiology have long beenassociated with schizophrenia and mood disorders. In schizophrenia,increased urinary levels of PEA (the so-called endogenous amphetamine),and alterations in the metabolism of tryptamine and p-tyramine have beenproposed, including enzymes involved in the synthetic and catabolicpathways of these molecules.

Therefore, the identification of specific receptors for trace aminescould lead to the development of specific drugs targeting this novelneuromodulator system with clinical applications in disorders such asschizophrenia, bipolar disorder and depression.

Recently, a family of G-protein coupled receptors has been identifiedand named Trace Amine-Associated Receptors (TAAR), TAAR1 being the bestcharacterized of these receptors, and the main target for endogenoustrace amines. TAAR1 is expressed in brain structures associated withpsychiatric disorders, in particular in key areas where modulation ofdopamine (ventral tegmental area) and serotonin (dorsal raphe) occursbut also in the amygdala, hypothalamus, nucleus accumbens, rhinalcortices, and subiculum. TAAR1 may be a novel target for antipsychoticdrugs with high potential for differentiation, exploring a fundamentallynew mechanism of action based on the modulation of dopaminergic andglutamatergic neurotransmission. Therefore, even in the absence of traceamine deficiencies, neuromodulatory effects on the monoaminergicpathways could predictably lead to an improvement in schizophrenia.Also, the TAAR genes map closely to one of the major geneticsusceptibility locus for schizophrenia, SCZD5.

LITERATURE

-   1. Davis B A, Boulton A A (1994) The trace amines and their acidic    metabolites in depression—an overview. Prog Neuropsychopharmacol    Biol Psychiatry 18, 17-45.-   2. Sabelli H, Fink P, Fawcett J, Tom C (1996) Sustained    antidepressant effect of PEA replacement. J Neuropsychiatry Clin    Neurosci 8,168-171.-   3. Borowsky B, Adham N, Jones K A, Raddatz R, Artymyshyn R, Ogozalek    K L, Durkin M M, Lakhlani P P, Bonini J A, Pathirana S, Boyle N, Pu    X, Kouranova E, Lichtblau H, Ochoa F Y, Branchek T A, Gerald    C (2001) Trace amines: identification of a family of mammalian G    protein-coupled receptors. Proc Nat Acad Sci USA 98, 8966-8971.-   4. Bunzow J R, Sanders M S, Arttamangkul S, Harrison L M, Zhang G,    Quigley D I, Darland T, Suchland K L, Pasumarnula S, Kennedy J L,    Olson S B, Magenis R E, Amara S G, Grandy D K (2001) Amphetamine,    3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and    metabolites of the catecholamine neurotransmitters are agonists of a    rat trace amine receptor. Mol Phaunacol 60, 1181-1188.-   5. Branchek T A, Blackburn T P (2003) Trace amine receptors as    targets for novel therapeutics: legend, myth and fact. Curr Opin    Pharmacol 3, 90-97.-   6. Lindemann L, Ebeling M, Kratochwil N A, Bunzow J R, Grandy D K,    Hoener M C (2005) Trace amine-associated receptors form structurally    and functionally distinct subfamilies of novel G protein-coupled    receptors. Genomics 85, 372-385.-   7. Lindemann L, Hoener M C (2005) A renaissance in trace amines    inspired by a novel GPCR family. Trends Pharmacol Sci 26,    274-281. S. Burchett S A, Hicks T P (2006) The mysterious trace    amines: protean neuromodulators of synaptic transmission in    mammalian brain. Prog Neurobiol 79, 223-246.-   9. Berry M D (2007) The potential of trace amines and their    receptors for treating neurological and psychiatric diseases. Rev    Recent Clin Trials 2, 3-19.-   10. Wolinsky T D, Swanson C J, Smith K E, Zhong H, Borowsky B,    Seeman P, Branchek T, Gerald C P (2007) The trace amine 1 receptor    knockout mouse: an animal model with relevance to schizophrenia.    Genes Brain Behav 6, 628-639.-   11. Lindemann L, Meyer C A, Jeanneau K, Bradaia A, Ozmen L,    Bluethmann H, Bettler B, Wettstein J G, Borroni E, Moreau J L,    Hoener M C (2008) Trace amine-associated receptor 1 modulates    dopaminergic activity. J Pharmacol Exp Ther 324, 948-956.-   12. Xie Z, Miller G M (2009) Trace amine-associated receptor 1 as a    monoaminergic modulator in brain. Biochem Pharmacol 78,1095-1104.-   13. Sotnikova T D, Caron M G, Gainetdinov R R (2009) Trace    amine-associated receptors as emerging therapeutic targets. Mol    Pharmacol 76, 229-235.-   14. Bradaia A, Trube G, Stalder H, Norcross R D, Ozmen L, Wettstein    J G, Pinard A, Buchy D, Gassmann M, Hoener M C, Bettler B (2009) The    selective antagonist EPPTB reveals TAAR1-mediated regulatory    mechanisms in dopaminergic neurons of the mesolimbic system. Proc    Natl Acad Sci USA 106, 20081-20086.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical combination for thetreatment of schizophrenia and acute manic episodes associated withbipolar disorders, which comprises a compound that is active on a traceamine-associated receptor 1 (TAAR1 agonist) and an antipsychotic drug.Such a combination can reduce metabolic side effects which appear whenusing an antipsychotic drug alone.

A combination of an antipsychotic drug with a trace amine-associatedreceptor 1 agonist has the potential to reduce the incidence ofmetabolic syndrome and positive symptoms in schizophrenia as well asacute manic episodes associated with bipolar disorders.

Based on the above, TAAR1 agonists should be effective agents in thetreatment of psychiatric disorders, both directly as well as indirectlyby influencing monoaminergic pathways. TAAR1 agonists that have beenextensively profiled in non-clinical experiments indicative ofantipsychotic, procognitive, antidepressant, and anti-addictiveactivity, leading to the thought that it may constitute a completely newclass of drugs for the treatment of schizophrenia and mood disorders.Based on this profile, TAAR1 agonists may have the potential to treatschizophrenic patients with better efficacy, including amelioratingnegative and cognitive symptoms which are not currently treatable withexisting therapies, and possibly reducing substance abuse in thesepatients. Finally, given its beneficial metabolic, anti-diabeticeffects, these drugs could provide significant benefits forschizophrenic patients, allowing the control of positive symptomswithout increasing metabolic syndrome.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIB. 1B illustrates the effects of TAAR1 agonists S1 and S2,respectively, on cocaine-induced locomotion in mice.

FIG. 2 illustrates the effects of TAAR1 agonist S2 on L-687414-inducedlocomotion in mice.

FIG. 3 illustrates synergism of S2 with increasing doses of olanzapinein L-687414-induced locomotion in mice.

FIG. 4A and FIG. 4B illustrates the effects of S1 on glucose and insulinAUC, respectively, in oGTT in mice.

FIG. 5A and FIG. 5B illustrates the effects of S2 on glucose and insulinAUC, respectively, in oGTT in mice.

FIG. 6A and FIG. 6B illustrates the effects of S3 on glucose and insulinAUC, respectively, in oGTT in mice.

FIG. 7A and FIG. 7B illustrates the effects of S4 on glucose and insulinAUC, respectively, in oGTT in mice.

FIG. 8 illustrates the effects of S5 on glucose AUC in oGTT in mice.

FIG. 9A illustrates the effects of S6, S7, and S8 (10 mg/kg, p.o. each)on glucose AUC in oGTT in mice. FIG. 9B illustrates the effects of S6and S8 (30 mg/kg, p.o. each) on glucose AUC in oGTT in mice.

FIG. 10A illustrates the effects of S9; and S 10, and S11 on glucose AUCin oGTT in mice. FIG. 10B illustrates the effects of S11 (1 mg/kg, and 3mg/kg, p.o. each) on glucose AUG in oGTT in mice.

FIG. 11A illustrates the effects of S12 and S13 (at 3 mg/kg, p.o.) onglucose AUC in oGTT in mice. FIG. 11B illustrates the effects of S14,S15, and S16 (at 1 mg/kg, p.o.) on glucose AUC in oGTT in mice.

FIG. 12 illustrates the effects of S17 (0.3 and 1 mg/kg, p.o.) onglucose AUC in oGTT in mice.

FIG. 13A illustrates the effects of S2 (3 and 10 mg/kg, p.o.) oncumulative weight gain in rats. FIG. 13B illustrates the effects of S2(1 mg/kg, p.o.), olanzapine (2 mg/kg, p.o.) and the combination of S2 (1mg/kg, p.o.) and olanzapine (2 mg/kg, p.o.) on cumulative weight gain inrats.

FIG. 14A illustrates the effects of S2 (3 and 10 mg/kg, p.o.) on fatmass content in rats. FIG. 14B illustrates the effects, respectively, ofS2 (1 mg/kg, p.o.), olanzapine (2 mg/kg, p.o.) and the combination of S2(1 mg/kg, p.o.) and olanzapine (2 mg/kg, p.o.) on fat mass in rats. FIG.14C illustrates the percent drug-induced change in fat mass vs.pre-treatment and control.

DETAILED DESCRIPTION OF THE INVENTION

From the group of TAAR1 agonists compounds have been selected, which aredescribed in WO08/092,785, WO08/098,857, WO2010/010014 andPCT/EP2010/070045 and are of the following structures:

wherein

-   R¹ is hydrogen, deuterium, tritium, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkyl    substituted by halogen, C₁₋₇-alkoxy substituted by halogen, halogen,    phenyl optionally substituted by halogen, or is phenyloxy, benzyl,    benzyloxy, —COO—C₁₋₇-alkyl, —O—(CH₂)_(o)—O—C₁₋₇-alkyl,    NH-cycloalkyl, cycloalkyl or tetrahydropyran-4-yloxy, wherein the    substituents for n>1 are the same or different;-   X is a bond, —CHR—, —CHRCHR′—, —OCH₂—, —NRCHR′, —OCHRCHR′,    —CH₂OCHR—, —CH₂CH₂CH₂—, —SCH₂—, —S(O)₂CH₂—, —CH₂SCH₂—, —CH₂N(R)CH₂—,    -cycloalkyl-CH₂— or SiRR′—CH₂—;-   R and R′ are each independently hydrogen, C₁₋₇-alkyl or C₁₋₇-alkyl    substituted by halogen;-   R² is hydrogen, phenyl or C₁₋₇-alkyl;-   Y is phenyl, naphthyl, thiophenyl, pyridinyl, cycloalkyl,    1,2,3,4-tetrahydro-naphthalen-2-yl, 2,3-dihydrobenzo[1,4]dioxin-6-yl    or benzo[1,3]dioxol-5-yl;-   n is 0, 1, 2 or 3;-   o is 2 or 3;-   or a pharmaceutically suitable acid addition salt.

More specifically, the TAAR1 receptor agonists are of the followingstructure

-   wherein-   R¹ is hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, C₁₋₇-alkyl    substituted by halogen, C₁₋₇-alkoxy substituted by halogen or    halogen, wherein the substituents for n=2 are the same or different;-   X is a bond, —NRCHR′, —CHRCHR′ or —OCHRCHR′;-   R and R′ are each independently hydrogen, C₁₋₇-alkyl;-   n is 1 or 2;-   or are compounds of formula

-   wherein-   R is hydrogen or C₁₋₇-alkyl;-   R¹ is —(CH₂)_(n)—(O)_(o)-heterocycloalkyl, optionally substituted by    C₁₋₇-alkyl, hydroxy, halogen, or by —(CH₂)_(p)-aryl;-   n is 0, 1 or 2;-   o is 0 or 1;-   p is 0, 1 or 2;-   R² is cycloalkyl, heterocycloalkyl, or is aryl or heteroaryl,    wherein the aromatic rings are optionally substituted by one or two    substituents, selected from C₁₋₇-alkyl, halogen, heteroaryl, CF₃,    OCF₃, OCH₂CF₃, C₁₋₇-alkoxy, CH₂—C₁₋₇-alkoxy, C₂₋₇-alkynyl or cyano;-   X is a bond, —NR′—, —CH₂NH—, —CHR″—, —(CH₂)_(q)—O— or —(CH₂)₂—;-   R′ is hydrogen or C₁₋₇-alkyl,-   R″ is hydrogen, C₁₋₇-alkyl, C₁₋₇alkoxy,-   q is 0, 1 or 2;-   or a pharmaceutically suitable acid addition salt thereof.-   or are more specifically compounds of formula II-1

-   wherein-   R is hydrogen;-   R¹ is pyrrolidinyl;-   R² is aryl or heteroaryl, wherein the aromatic rings are optionally    substituted by halogen;-   X is a bond or —NR′—;-   R′ is hydrogen or C₁₋₇-alkyl,-   or a pharmaceutically suitable acid addition salt thereof.

The term “alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 12 carbon atoms, in particular of 1 to 7carbon atoms, more particular of 1 to 4 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, ortert-butyl. The term “C₁₋₇-alkyl” denotes and alkyl group having from 1to 7 carbon atoms.

As used herein, the term “C₁₋₇-alkoxy” denotes a group wherein the alkylresidue is as defined above and which is attached via an oxygen atom.

As used herein, the term “C₁₋₇-alkyl substituted by halogen” denotes analkyl group as defined above, wherein at least one hydrogen atom isreplaced by halogen, for example CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CH₂CF₃,CH₂CF₂CF₃ and the like.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “cycloalkyl” denotes an alkylene ring, containing from 3 to 6carbon ring atoms.

The term “alkynyl” denotes a straight-chain or branched hydrocarbonresidue comprising a triple bond and up to 7, preferably up to 4 carbonatoms, such as e.g. ethynyl or 2-propynyl.

The term “aryl”, denotes an aromatic carbon ring system having 6 to 12ring atoms, such as phenyl or naphthyl, preferably phenyl.

The term “heteroaryl” refers to an aromatic 5 to 6 membered monocyclicring or 9 to 10 membered bicyclic ring which contains 1, 2 or 3heteroatoms selected from nitrogen, oxygen and/or sulphur, for example,pyridinyl, pyrazolyl, pyrimidinyl, benzoimidazolyl, quinolinyl andisoquinolinyl.

The term “heterocycloalkyl” denotes a non-aromatic 5 to 6 memberedmonocyclic ring which contains 1, 2 or 3 heteroatoms selected fromnitrogen, oxygen and/or sulphur, for example piperazinyl, piperidinyl,morpholinyl, pyrrolidinyl and thiomorpholinyl.

The term “pharmaceutically acceptable” denotes an attribute of amaterial which is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic, and neither biologically nor otherwiseundesirable and is acceptable for veterinary as well as humanpharmaceutical use.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

The term “therapeutically effective amount” denotes an amount of acompound of the present invention that, when administered to a subject,(i) treats or prevents the particular disease, condition or disorder,(ii) attenuates, ameliorates or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, conditionor disorder described herein. The therapeutically effective amount willvary depending on the compound, disease state being treated, theseverity or the disease treated, the age and relative health of thesubject, the route and form of administration, the judgement of theattending medical or veterinary practitioner, and other factors.

Specific compounds, which have been used in the examples as describedbelow, are the followings:

S1=(S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine;S2=(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine;S3=(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine;S4=(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine;S5=3-[(S)-1-(S)-2-amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol;S6=5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide;S7=4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide;S8=1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea;S9=(S)-4-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine;S10=5-chloro-pyrimidine-2-carboxylic acid{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;S11=N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;S12=(R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;S13=(S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;S14=(S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;S15=(S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;S16=(S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; andS17=(S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.

The specific combination of an antipsychotic drug, especiallyolanzapine, and a TAAR1 agonist as mentioned above may reduce someundesired metabolic side effects.

In one embodiment, the invention provides the combination of an atypicalantipsychotic drug and a TAAR1 agonist, wherein the preferred atypicalantipsychotic drug is olanzapine and the preferred TAAR1 agonist is acompound of formulas I, I-1, II or II-1. More specifically, the TAAR1agonist is a compound selected from S1 to S17.

In another embodiment, the invention provides the novel compound S2,which is (S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine,encompassed by formulas I or I-1. In still another embodiment, theinvention provides the combination comprising olanzapine and a TAAR1agonist for the treatment of schizophrenia and manic episodes associatedwith bipolar disorders with reduced incidence of metabolic syndrome,wherein the reduced incidence of metabolic syndrome results fromantidiabetic efficacy with lowering blood glucose excursion, fat massand body weight.

In yet another embodiment, the invention provides the use of acombination comprising olanzapine and a TAAR1 agonist for the treatmentof schizophrenia and manic episodes associated with bipolar disorderswith reduced incidence of metabolic syndrome, wherein the reducedincidence of metabolic syndrome results from antidiabetic efficacy withlowering blood glucose excursion, fat mass and body weight.

In another embodiment, the invention provides the use of a combinationcomprising olanzapine and a TAAR1 agonist for the manufacture of amedicament for the treatment of schizophrenia and manic episodesassociated with bipolar disorders with reduced incidence of metabolicsyndrome, wherein the reduced incidence of metabolic syndrome resultsfrom antidiabetic efficacy with lowering blood glucose excursion, fatmass and body weight.

In one embodiment, the present invention provides a method for thetreatment of schizophrenia and manic episodes associated with bipolardisorders with reduced incidence of metabolic syndrome, wherein thereduced incidence of metabolic syndrome results from antidiabeticefficacy with lowering blood glucose excursion, fat mass and waistcomprising administering to a human in need thereof an effective amountof a combination comprising an atypical antipsychotic drug and a TAAR1agonist.

In another embodiment, the present invention provides a method for thetreatment of schizophrenia and manic episodes associated with bipolardisorders with reduced incidence of metabolic syndrome, wherein thereduced incidence of metabolic syndrome results from antidiabeticefficacy with lowering blood glucose excursion, fat mass and waist,wherein the atypical antipsychotic drug is olanzapine and the TAAR1agonists are as described in formulas I, I-1, II and II-1.

In still another embodiment, the present invention provides apharmaceutical composition comprising a combination of an atypicalantipsychotic drug and a TAAR1 agonist as described in formulas I, I-1,II and II-1, together with pharmaceutically acceptable excipients forthe treatment of schizophrenia and manic episodes associated withbipolar disorders with reduced incidence of metabolic syndrome, whereinthe reduced incidence of metabolic syndrome results from antidiabeticefficacy with lowering blood glucose excursion, fat mass and bodyweight.

The TAAR1 agonists can be prepared as follows:

Example S1 (S)-4-((S)-2-Phenyl-butyl)-4,5-dihydro-oxaza-2-ylamine

a) (R)-1-Iodomethyl-propyl)-benzene

To a solution of triphenylphosphine (15.4 g, 59 mmol) and imidazole(3.99 g, 59 mmol) in dichloromethane (150 ml) at room temperature wasadded portionwise iodine (14.9 g, 50 mmol) at such a rate that thetemperature of the reaction mixture did not rise above 30° C. To themixture was then added a solution of (R)-2-phenyl-butan-1-ol (7.34 g, 41mmol, CAS 16460-75-6) in dichloromethane (50 ml) and the mixture wasthen stirred at room temperature overnight. The mixture was thenconcentrated in vacuo and the residue was resuspended in ether and theresulting crystals collected by filtration. The filtrate wasconcentrated in vacuo and the residue was triturated in heptane. Theresulting crystals were removed by filtration and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, heptane/EtOAc) to yield a colourless oil, (6.38 g, 60%).

b)(2R,5S)-2-Isopropyl-1-3,6-dimethoxy-5-((S)-2-phenyl-butyl)-2,5-dihydro-pyrazine

A solution of (2R)-(−)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine(4.25 g, 23.1 mmol) in tetrahydrofuran (30 ml) was cooled to −78° C.,then n-butyllithium (1.6 M in hexane, 15.1 ml, 24.2 mmol) was added andthe mixture was stirred for 1 hour. A solution of((R)-1-iodomethyl-propyl)-benzene (6.30 g, 24.2 mmol) in tetrahydrofuran(30 ml) was added dropwise over 30 min and the mixture was stirredovernight while being allowed to warm slowly from −70° C. to roomtemperature. The reaction was quenched by addition of saturated aqueousammonium chloride solution and the mixture was extracted with ether. Theorganic layer was separated, washed with saturated brine, then driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, heptane/EtOAc) to yield a light yellow oil(4.69 g, 64%); MS (ISP): 317.0 ([M+H]⁺).

c) (2S,4S)-2-Amino-4-phenyl-hexanoic acid methyl ester

To a solution of trifluoroacetic acid (3.4 ml) in water (440 ml) wasadded dropwise over 15 min a solution of(2R,5S)-2-isopropyl-3,6-dimethoxy-5-((S)-2-phenyl-butyl)-2,5-dihydro-pyrazine(4.69 g, 14.8 mmol) in acetonitrile (75 ml). The mixture was stirredovernight at room temperature then made basic by addition of saturatedaqueous sodium carbonate solution and the mixture was extracted withethyl acetate. The phases were separated and the organic phase waswashed sequentially with water and with saturated brine, then dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, EtOAc/heptane) to yield a yellow oil (2.78g, 85%); MS (ISP): 222.1 ([M+H]⁺).

d) (2S,4S)-2-Amino-4-phenyl-hexan-1-ol

To a suspension of lithium aluminum hydride (121 mg, 3.18 mmol) intetrahydrofuran (8 ml) was added a solution of(2S,4S)-2-amino-4-phenyl-hexanoic acid methyl ester (320 mg, 1.45 mmol)in tetrahydrofuran (10 ml) and the mixture was stirred for 16 hours. Thereaction was quenched by dropwise addition of ethyl acetate, thenacidified to pH 5 by addition of hydrochloric acid and then made basicby addition of saturated aqueous sodium bicarbonate solution. Themixture was taken up in ethyl acetate/tetrahydrofuran (1:1), the phaseswere separated and the organic phase was washed sequentially with waterand with saturated brine. The organic phase was then dried over Na₂SO₄and concentrated in vacuo. The residue was purified by chromatography(column: Isolute® Flash-NH₂ from Separtis; eluent: dichloromethane/MeOH)to yield a yellow oil, (116 mg, 42%); MS (ISP): 194.4 ([M+H]⁺).

e) (S)-4-((S)-2-Phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine

To a stirred, cooled (0° C.) solution of(2S,4S)-2-amino-4-phenyl-hexan-1-ol (270 mg, 1.40 mmol) and sodiumacetate (229 mg, 2.70 mmol) in methanol (20 ml) was added dropwise asolution of cyanogen bromide (180 mg, 1.68 mmol) in methanol (2 ml) over10 min. The mixture was then allowed to warm to r.t. and stirring wascontinued for 16 h. The mixture was concentrated in vacuo and theresidue was taken up in ethyl acetate and washed sequentially withsaturated aqueous sodium bicarbonate solution and with saturated brine.The organic phase was dried over sodium sulphate and concentrated invacuo. The residue was purified by chromatography (column: Isolute®Flash-NH₂ from Separtis; eluent: heptane/EtOAc/MeOH) to yield a lightyellow solid. MS (ISP): 219.3 ([M+H]⁺).

S2 (S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine

a) (RS)-Amino-(3-fluoro-2-methyl-phenyl)-acetonitrile

To a stirred solution of 3-fluoro-2-methyl-benzaldehyde (5.0 g) inmethanol (20 ml) were added sequentially ammonia solution (40.5 ml, 7 Msolution in methanol) and tetraisopropyl orthotitanate (12.6 ml) and theresulting mixture was stirred at r.t. for 1 h. Trimethylsilylcyanide(4.69 ml) was then added dropwise and stirring continued at r.t.overnight. The reaction mixture was poured onto ice-water (400 ml) andthe mixture was then extracted twice with ethyl acetate. The combinedorganic phases were washed with brine and then dried over sodiumsulphate and concentrated in vacuo to afford(RS)-amino-(3-fluoro-2-methyl-phenyl)-acetonitrile (5.90 g, quant.) asan orange solid. ¹H NMR δ (CDCl₃, 300 MHz): 7.39 (1H, d, J=7.3 Hz), 7.31(1H, m), 7.17 (1H, dd, J=9.6 & 9.6 Hz), 5.16 (1H, t, J=7.8 Hz), 5.16(1H, d, J=7.8 Hz), 2.26 (1H, d, J=2.1 Hz).

b) (RS)-Amino-(3-fluoro-2-methyl-phenyl)-acetic acid

(RS)-Amino-(3-fluoro-2-methyl-phenyl)-acetonitrile (5.89 g) wassuspended in 5 N aq hydrochloric acid (40 ml) and the mixture was heatedat reflux for 18 h. The mixture was then extracted with ethyl acetateand the aqueous phase was concentrated in vacuo. The residue wasresuspended in isopropanol and concentrated in vacuo again. The residuewas taken up in water and neutralised by dropwise addition of 1 N aqNaOH, whereby white crystals slowly formed. The crystals were collectedby filtration and dried in vacuo at 50° C. to afford(RS)-amino-(3-fluoro-2-methyl-phenyl)-acetic acid (7.1 g, quant.) as anoff-white solid. MS (ISP): 184.1 ([M+H]⁺).

c) (RS)-2-Amino-2-(3-fluoro-2-methyl-phenyl)-ethanol

To a stirred solution of lithium borohydride in THF (48.9 ml, 2 Msolution) under an argon atmosphere was added dropwisechlorotrimethylsilane (25.0 ml). The resulting suspension was cooled to0° C. and (RS)-amino-(3-fluoro-2-methyl-phenyl)-acetic acid (7.1 g) wasadded portionwise, whereby the temperature of the reaction mixture rosetransiently to 45° C. The ice bath was removed and stirring was thencontinued at r.t. for 90 min. The mixture was quenched by dropwiseaddition of methanol (20 ml) and then concentrated in vacuo. The residuewas suspended in ethyl acetate and washed with 2 N aq NaOH. The phaseswere separated and the aqueous phase was extracted with ethyl acetate.The combined organic phases were dried over sodium sulphate andconcentrated in vacuo to afford(RS)-2-amino-2-(3-fluoro-2-methyl-phenyl)-ethanol (1.83 g, 28%) as alight yellow solid. MS (ISP): 170.3 ([M+H]⁺).

d) (RS)-4-(3-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine

To a stirred, cooled (0° C.) solution of(RS)-2-amino-2-(3-fluoro-2-methyl-phenyl)-ethanol (1.82 g) and sodiumacetate (1.72 g) in methanol (17 ml) was added dropwise a solution ofcyanogen bromide (1.18 g) in methanol (8 ml) over 10 min. The mixturewas then stirred for 1 h at 0° C., then was allowed to warm to at r.t.and stirring continued for 2 b. The mixture was concentrated in vacuoand the residue was resuspended in water and made basic by addition of 1M aq sodium hydroxide solution. The mixture was then extracted twicewith dichloromethane and the combined organic phases were dried oversodium sulphate and concentrated in vacuo.

The residue was purified by column chromatography (SiO₂; gradient:dichloromethane/methanol) to give(RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (0.85 g,41%) as a light yellow solid. MS (ISP): 195.3 ([M+H]⁺).

e) (+)-(S)-4-(3-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine &(−)-(R)-4-(3-Fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine

(RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine wasseparated by chiral HPLC (Chiralpak AD, EtOH/heptane=10:90) to yield(−)-(R)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (whitesolid; MS (ISP): 195.3 ([M+H]⁺)) as the first fraction and(+)-(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (whitesolid; MS (ISP): 195.3 ([M+H]⁺)) as the second fraction.

S3(+)-(S)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine

a)(RS)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine

This was prepared in analogy to example S2 (steps a-d) starting from4-chloro-2-trifluoromethyl-benzaldehyde in place of3-fluoro-2-methyl-benzaldehyde. White solid. MS (ISP): 267.1([{³⁷Cl}M+H]⁺), 265.0 ([{³⁵Cl}M+H]⁺).

b)(+)-(S)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine&(−)-(R)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine

(RS)-4-(4-Chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylaminewas separated by chiral HPLC (Chiralpak AD, EtOH/heptane=5:95) to yield(+)-(S)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylamine(white solid; MS (ISP): 267.1 ([{³⁷Cl}M+H]⁺), 265.0 ([{³⁵Cl}M+H]⁺)) asthe first fraction and(−)-(R)-4-(4-chloro-2-trifluoromethyl-phenyl)-4,5-dihydro-oxazol-2-ylanaine(white solid; MS (ISP): 267.1 ([{³⁷Cl}M+H]⁺), 265.0 ([{³⁵Cl}M+H]⁺)) asthe second fraction.

S4 (S)-4-[(Ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine

a)(S)-4-[(Ethyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a stirred solution of tert-butyl(R)-(+)-4-formyl-2,2-dimethyl-3-oxazolinecarboxylate (681 mg, CAS95715-87-0) at r.t. in 1,2-dichloroethane (10 ml) under an argonatmosphere were added molecular sieves 4 Å (1.5 g) and N-ethylaniline(025 ml). After stirring for 15 min at r.t., sodiumtriacetoxyborohydride (1.68 g) was added in one portion, followed byacetic acid (5 drops) and stirring at r.t. was continued overnight. Themixture was quenched by the careful addition of 10% KHCO₃ (15 ml). Thebiphasic mixture was stirred at r.t. for 20 min and filtered. Theaqueous phase of the filtrate was back extracted with CH₂Cl₂. Thecombined organics were washed with H₂O and brine, dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography (SiO₂; gradient: cyclohexane->cyclohexane/EtOAc4:1) to give(S)-4-[(ethyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (469 mg, 57%) as an orange viscous oil. MS (ISP):335.5 ([M+H]⁺)

b) (S)-2-Amino-3-(ethyl-phenyl-amino)-propan-1-ol

To a stirred solution of(S)-4-[(ethyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (462 mg) at r.t. in dioxane (5.85 ml) under anargon atmosphere was added HCl solution (4 M in dioxane; 4.14 ml). Themixture was stirred at r.t. overnight and concentrated. The residue wastaken up in EtOAc and washed with 10% aq. potassium bicarbonatesolution. The aqueous layer was back extracted with EtOAc. The combinedorganics were washed with water and then with brine, dried over MgSO₄and concentrated in vacuo. The crude product was purified by columnchromatography (Isolute® SPE flash NH₂ column,aminopropyl-functionalized silica; CH₂Cl₂/MeOH 9:1) to give(S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (133 mg, 62%) as a lightbrown viscous oil. MS (ISP): 195.1 ([M+H]⁺)

c) (S)-4-[(Ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine

To a stirred solution of (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol(128 mg) at r.t. in THF (5 ml) under an argon atmosphere were addedpotassium carbonate (182 mg) and a solution of cyanogen bromide (140 mg)in THF (5 ml). Stirring at r.t. was continued for 21 h. The mixture(off-white suspension) was diluted with EtOAc and washed with H₂O. Theaqueous phase was back extracted with EtOAc. The combined organics werewashed with brine, dried over MgSO₄, filtered and concentrated in vacuo.The crude product was purified by column chromatography (Isolute® SPEflash NI-12 column, aminopropyl-functionalized silica; gradient:CH₂Cl₂->CH₂Cl₂/MeOH 9:1) to provide(S)-4-[(ethyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine (108mg, 75%) as an off-white solid. MS (ISP): 220.4 ([M+H]⁺)

S5 3-[(S)-1-((S)-2-Amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol

a) (S)-4-((R)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester and(S)-4-((S)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester

To a stirred solution of(S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acidtert-butyl ester (15.5 g; CAS 147959-19-1) in dry diethyl ether (100 ml)under an argon atmosphere at room temperature was added dropwise asolution of ethylmagnesium bromide in diethyl ether (42.6 ml, 3 Msolution) and stirring continued for 1 hour. The reaction mixture wasthen quenched by careful addition of water (10 ml) and the mixture wasthen filtered through decalite. The filtrate was washed sequentiallywith water and with saturated brine and then the organic phase wasseparated, dried over sodium sulphate, filtered and concentrated invacuo. The reside was purified by column chromatography (SiO₂; gradient:heptane/EtOAc 100:0 50:50) to give(S)-4-((R)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester (7.30 g) from fractions eluting first and(S)-4-((S)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester (6.44 g) from fractions eluting later, both compoundsas colourless oils.(S)-4-((R)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester: ¹H NMR δ (CDCl₃, 300 MHz): 4.52 (1H, br. D, J=3.3 Hz),4.23 (1H, m), 4.00 (1H, dd, J=8.7 & 5.4 Hz), 3.66 (1H, d, J=8.7 Hz),3.40 (1H, m), 1.79 (1H, td, J=11.4 & 2.1 Hz), 1.60-1.44 (16H, m), 0.95(3H, t, J=7.5 Hz).(S)-4-((S)-2-Hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester: ¹H NMR δ (CDCl₃, 300 MHz): 4.12 (1H, m), 3.98 (1H, dd,J=9.0 & 5.7 Hz), 3.82 (1H, m), 3.55 (1H, m), 2.88 (1H, br. s), 1.79 (1H,m), 1.70-1.40 (16H, m), 0.95 (3H, t, J=7.5 Hz).

b)(S)-4-[(S)-2-(3-Benzyloxy-phenoxy)-butyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a stirred solution of 3-benzyloxy-phenol (264 mg) in THF (5 ml) wereadded sequentially friphenylphosphine (364 mg) and di-tert-butylazodicarboxylate (309 mg) and the resulting yellow solution was stirredat room temperature for 15 min. A solution of(S)-4-((R)-2-hydroxy-butyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester (300 mg) in THF (5 ml) was then added dropwise and theresulting mixture was stirred at 70° C. for 90 min. The reaction mixturewas cooled to room temperature and concentrated in vacuo. The crudeproduct was purified by column chromatography (SiO₂; gradient:heptane/EtOAc 100:0→70:30) to give(S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (1.35 g, 34%) as a colourless viscous oil. MS(ISP): 456.4 ([M+H]⁺).

c) (2S,4S)-2-Amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol

To a solution of trifluoroacetic acid (0.07 ml) in water (6 ml) wasadded dropwise a solution of(S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (135 mg) in acetonitrile (1 ml). The mixture washeated for 4 h at 80° C. with mechanical shaking. The mixture was thencooled to room temperature and diluted with 1 N aqueous sodium hydroxidesolution. The mixture was extracted twice with ethyl acetate and thecombined organic phases were dried over sodium sulphate and concentratedin vacuo to give (2S,4S)-2-amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol (94mg, quant.) as a light yellow viscous oil. MS (ISP): 316.1 ([M+H]⁺).

d)(S)-4-[(S)-2-(3-Benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine

To a stirred mixture of(2S,4S)-2-amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol (90 mg) and sodiumacetate (46 mg) in methanol (2 ml) under an argon atmosphere was added asolution of cyanogen bromide (37 mg) in methanol (1 ml). The mixture wasstirred for 18 hours then diluted with 1 N aqueous sodium hydroxidesolution. The mixture was extracted twice with dichloromethane and thecombined organic phases were dried over sodium sulphate and concentratedin vacuo. The crude product was purified by column chromatography(column: Isolute® Flash-NH₂ from Separtis; gradient:dichloromethane/MeOH 100:0→95:5) to afford(S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine(69 mg, 71%) as a light yellow gum. MS (ISP): 341.1 ([M+H]⁺).

e) 3-[(S)-1-((S)-2-Amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol

To a solution of(S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-4,5-dihydro-oxazol-2-ylamine(60 mg) in methanol (3 ml) at room temperature was added 10% palladiumon charcoal (19 mg). The mixture was stirred under an atmosphere ofhydrogen (1 atm) at room temperature for 1 h. The catalyst was removedby filtration through decalite, washing with methanol and withdichloromethane, and the filtrate was concentrated in vacuo to yield3-[(S)-1-((S)-2-amino-4,5-dihydro-oxazol-4-ylmethyl)-propoxy]-phenol asa white solid (44 mg, quant.); MS (ISP): 251.2 ([M+H]⁺).

S6 (RS)-4-Chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide hydrochloride

(RS)-3-[4-(4-Chloro-benzoylamino)-phenyl]-pyrrolidine-1-carboxylic acidtert-butyl ester

To a stirred suspension of (RS)-tert-butyl3-(4-aminophenyl)pyrrolidine-1-carboxylate (1.9 g, CAS 908334-28-1) inTHF (50 ml) were added sequentially triethylamine (2.0 ml) and4-chloro-benzoyl chloride (0.93 ml) and stirring was continued at roomtemperature for 3 h. The mixture was then diluted with ethyl acetate.Water was added and the mixture was acidified to pH 1 by addition of 1 Maq. hydrochloric acid. The organic phase was separated and washedsequentially with aqueous sodium hydroxide solution and with saturatedbrine. The organic phase was then dried over sodium sulphate andconcentrated in vacuo to give(RS)-3-[4-(4-chloro-benzoylamino)-phenyl]-pyrrolidine-1-carboxylic acidtert-butyl ester (2.42 g, 83%) as a white solid which was used in thenext step without further purification.

b) (RS)-4-Chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide hydrochloride

To a stirred solution of(RS)-3-[4-(4-chloro-benzoylamino)-phenyl]-pyrrolidine-1-carboxylic acidtert-butyl ester (2.36 g) in THF (30 ml) was added dropwise a solutionof hydrogen chloride in dioxane (22 ml, 4 M solution) and the mixturewas heated at 60° C. overnight. The mixture was then cooled to 0° C. andthe ensuing crystals were collected by filtration, washing with diethylether, and then dried in vacuo at 60° C. to afford(RS)-4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide hydrochloride (1.65g, 83%) as a white crystalline solid. MS (ISP): 303.2 ([{³⁷Cl}M+H]⁺),301.3 ([{³⁵Cl}M+H]⁺).

S7 (RS)-1-(5-Chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)-ureahydrochloride

a)(RS)-3-{4-[3-(5-Chloro-pyridin-2-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

To a stirred suspension of 2-amino-5-chloro-pyridine (1.01 g) indichloroethane (20 ml) was added portionwise triphosgene (831 mg).Triethylamine (2.22 ml) was then added dropwise and the mixture wasstirred at 50° C. for 1 h. The mixture was then concentrated in vacuo toafford a beige solid containing a mixture of triethylammonium chlorideand 5-chloro-2-isocyanato-pyridine. This solid was then added to astirred solution of (RS)-tert-butyl3-(4-aminophenyl)pyrrolidine-1-carboxylate (350 mg, CAS 908334-28-1) andN,N-diisopropylethylamine (0.68 ml) in dichloroethane (6 ml) and theresulting mixture was stirred at 60° C. overnight. The mixture was thendiluted with dichloromethane and washed with water. The phases wereseparated and the organic phase was dried over sodium sulphate andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂; gradient: heptane/EtOAc) to give(RS)-3-{4-[3-(5-chloro-pyridin-2-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (212 mg, 38%) as an off-white solid. MS (ISP):419.2 ([{³⁷Cl}M+H]⁺), 417.2 ([{³⁵Cl}M+H]⁺).

b) (RS)-1-(5-Chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)-ureahydrochloride

To a stirred solution of(RS)-3-{4-[3-(5-chloro-pyridin-2-yl)-ureido]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (210 mg) in THF (4 ml) was added dropwise asolution of hydrogen chloride in dioxane (1.89 ml, 4 M solution) and themixture was heated at 60° C. overnight. The mixture was then cooled to0° C. and the ensuing crystals were collected by filtration, washingwith ethyl acetate, and were dried in vacuo at 60° C. to afford(RS)-1-(5-chloro-pyridin-2-yl)-3-(4-pyrolidin-3-yl-phenyl)-ureahydrochloride (167 mg, 94%) as a beige crystalline solid. MS (ISP):319.1 ([{³⁷Cl}M+H]⁺), 317.2 ([{³⁵Cl}M+H]⁺).

S8 (RS)-5-Chloro-pyridine-2-carboxylic acid(4-pyrrolidin-3-yl-phenyl)-amide hydrochloride

a)(RS)-3-{4-[(5-Chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

To a stirred suspension of (RS)-tert-butyl3-(4-aminophenyl)pyrrolidine-1-carboxylate (200 mg, CAS 908334-28-1) inDMF (10 ml) were added sequentially N-methylmorpholine (0.22 ml), TBTU(490 mg) and 5-chloro-2-pyridine carboxylic acid (180 mg) and themixture was stirred at room temperature for 90 min. The mixture was thendiluted with ethyl acetate and washed sequentially with 1 M aq.hydrochloric acid and with saturated brine. The phases were separatedand the organic phase was dried over sodium sulphate and concentrated invacuo. The residue was purified by column chromatography (SiO₂;gradient: heptane/EtOAc) to give(RS)-3-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (310 mg, quant.) as a white solid. MS (ISP): 421.3([M+NH₄]⁺), 419.2 ([M+NH₄]⁺).

b) (RS)-5-Chloro-pyridine-2-carboxylic acid(4-pyrrolidin-3-yl-phenyl)-amide hydrochloride

To a stirred solution of(RS)-3-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (310 mg) in THF (6 ml) was added dropwise asolution of hydrogen chloride in dioxane (2.9 ml, 4 M solution) and themixture was heated at 60° C. overnight. The mixture was then cooled to0° C. and the ensuing crystals were collected by filtration, washingwith diethyl ether, and were dried in vacuo at 60° C. to afford(RS)-5-chloro-pyridine-2-carboxylic acid(4-pyrrolidin-3-yl-phenyl)-amide hydrochloride as a light yellow solid.MS (ISP): 304.2 ([{³⁷Cl}M+H]⁺), 302.3 ([{³⁵Cl}M+H]⁺).

S9(S)-4-[(S)-1-(4-Fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine

a) 1-((S)-1-Allyloxy-ethyl)-4-fluoro-benzene

To a stirred suspension of sodium hydride (3.14 g, 55% dispersion inoil) in dry DMF (180 ml) under an argon atmosphere was added(S)-1-(4-fluorophenyl)-ethanol (8.41 g, CAS 101219-73-2). Allyl bromide(6.6 ml) was then added dropwise. The reaction mixture was stirred for30 min at room temperature and was then quenched by addition of water.The mixture was extracted with ethyl acetate twice. The combined organiclayers were dried (MgSO₄) and concentrated in vacuo. The crude productwas purified by column chromatography (SiO₂; gradient: heptane/EtOAc) togive 1-((S)-1-allyloxy-ethyl)-4-fluoro-benzene (8.66 g, 80%) as acolourless liquid. ¹H NMR (300 MHz, CDCl3, δ ppm): 1.43 (d, J=6.6 Hz,3H), 3.84 (m, 2H), 4.45 (q, J=6.6 Hz, 1H), 5.15 (dd, J₁=10.5 Hz, J₂=1.8Hz, 1H), 5.22 (dd, J₁=17.4 Hz, J₂=1.8 Hz, 1H), 5.89 (m, 1H), 7.03 (m,2H), 7.29 (m,

b) (S)-3-[(S)-1-(4-Fluoro-phenyl)-ethoxy]-propane-1,2-dial

AD-MIX-β (62.9 g) was stirred in t-BuOH/H2O 1:1 (440 ml) for 15 min atroom temperature and then cooled to 0° C. To this solution was added1-((S)-1-allyloxy-ethyl)-4-fluoro-benzene (8.00 g). The mixture wasstirred for 48 h at 0° C. The reaction mixture was treated with sodiumsulfite and stirred for 30 min at 0° C. and at room temperature for 1day. The solution was extracted with ethyl acetate twice. The combinedorganic layers were dried (MgSO₄) and concentrated in vacuo. The productwas purified by column chromatography (SiO₂; gradient: heptane/EtOAc 1/1to 0/1) to give an 80:20 mixture of(S)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propane-1,2-diol &(R)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propane-1,2-diol (8.59 g, 90%) asa light yellow liquid. ¹H NMR (300 MHz, CDCl₃, 8 ppm): 1.44 (d, J=6.6Hz, 3H), 2.1 (b, 1H), 2.6 (b, OH), 3.39 (m, 21-1), 3.60 (m, 1H), 3.64(m, 1H), 3.83 (m, 1H), 4.41 (q, J=6.6 Hz, 1H), 7.03 (m, 2H), 7.27 (m,2H).

c)(R)-1-(tert-Butyl-dimethyl-silanyloxy)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-2-ol

To a solution of the 80:20 mixture of(S)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propane-1,2-diol &(R)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propane-1,2-diol (8.40 g) intetrahydrofuran (84 ml) were added triethylamine (5.74 ml) and4-dimethylaminopyridine (479 mg). The mixture was cooled to 0° C. and asolution of tert-butyl(chloro)dimethylsilane (6.21 g) in tetrahydrofuran(17 ml) was added dropwise. After 2 hours at 0° C., the reaction mixturewas allowed to stir at room temperature for 16 hours. Water was addedand the mixture was extracted twice with diethyl ether. The combinedorganic layers were dried (MgSO₄) and concentrated in vacuo to give an80:20 mixture of(R)-1-(tert-butyl-dimethyl-silanyloxy)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-2-ol&(S)-1-(tert-butyl-dimethyl-silanyloxy)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-2-ol(12.6 g, 98%) as a yellow liquid. The crude product was used in the nextstep without further purification.

d)(S)-2-(tert-Butyl-dimethyl-silanyloxy)-1-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-ethylamine

To a stirred solution of the 80:20 mixture of(R)-1-(tert-butyl-dimethyl-silanyloxy)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-2-ol&(S)-1-(tert-butyl-dimethyl-silanyloxy)-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-2-ol(12.4 g) and triethylamine (6.84 ml) in dichloromethane (60 ml) at 0° C.was added dropwise a solution of methanesulfonyl chloride (3.52 ml) inTHF. The mixture was stirred for 1 hour at 0° C. and then water anddichloromethane were added. The aqueous phase was extracted a secondtime with dichloromethane, and the combined organic layers were washedwith brine and dried over MgSO₄. The solvent was evaporated and theproduct was dried under high vacuum. The resulting crude mesylateproduct (15.5 g) was dissolved in DMF (100 ml) and sodium azide (4.94 g)was added. The reaction mixture was stirred at 100° C. for 16 hours. Thereaction was then quenched with water and the mixture was extractedtwice with ethyl acetate. The combined organic layers were dried overMgSO4 and concentrated in vacuo. The crude azide product (15.6 g) wasdissolved in methanol (160 ml) and 10% palladium on charcoal (1.6 g) wasadded. The mixture was stirred under an atmosphere of hydrogen at roomtemperature for 2 hours. The catalyst was removed by filtration throughcelite and the filtrate was concentrated in vacuo to give an 80:20mixture of(S)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-ethylamine&(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-ethylamine(14.4 g, 100%) as a yellow liquid which was used in the next stepwithout further purification.

e) (R)-2-Amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol

To a stirred solution of the 80:20 mixture of(S)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-ethylamine&(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-[(S)-1-(4-fluoro-phenyl)-ethoxymethyl]-ethylamine(14.4 g) in THF (150 ml) at 0° C. was added tetrabutylammonium fluoride(22.9 ml, 1 M solution in THF) and the mixture was stirred at roomtemperature for 18 h. The solvent was evaporated and the crude productwas purified by column chromatography (column: Isolute® Flash-NH₂ fromSepartis; eluent: ethyl acetate) to give an 80:20 mixture of(R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol &(S)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (5.58 g, 60%)as a light yellow liquid. MS (ISP): 214.4 ([M+H]⁺).

f) (R)-2-Amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol(R)-hydroxy-phenyl-acetate

To a stirred solution of the 80:20 mixture of(R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol &(S)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (2.94 g) inisopropanol (3 ml) was added a solution of D-(−)-mandelic acid (2.10 g)in isopropanol (2 ml). The solvent was evaporated and replaced withethyl acetate to afford white crystals which were collected byfiltration. The crystals were dissolved in hot EtOAc (65 ml) at 80° C.and the mixture was allowed to cool slowly. Crystals appeared onreaching a temperature of 70° C. and the suspension was then stirred atroom temperature for 16 h. The crystals were collected by filtration andredissolved in hot EtOAc (80 ml) at 80° C. and the mixture was allowedto cool slowly until cyrstallisation started and then the resultingsuspension was stirred at room temperature for 16 h. The crystals werecollected by filtration to afford pure(R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol(R)-hydroxy-phenyl-acetate (3.08 g, 61%) as a white solid. ¹H NMR (300MHz, DMSO, δ ppm): 1.34 (d, J=6.3 Hz, 3H), 3.13 (m, 1H), 3.23 (m, 1H),3.37 (m, 4H), 3.83 (m, 1H), 4.46 (q, J=6.3 Hz, 1H), 4.54 (s, 1H), 7.20(m, 5H), 7.35 (m, 4H).

g)(S)-4-[(S)-1-(4-Fluoro-phenyl)-ethoxymethyl]-4,5-dihydro-oxazol-2-ylamine

A suspension of(R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol(R)-hydroxy-phenyl-acetate in EtOAc was treated with aqueous sodiumbicarbonate solution and the mixture was stirred at room temperatureuntil all the solid had dissolved. The phases were separated and theorganic layer was dried over MgSO₄. The solvent was evaporated to afford(R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol as the freebase.

To a stirred solution of(R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (1.40 g) inTHF (80 ml) were added sequentially K₂CO₃ (1.82 g) and cyanogen bromide(0.83 g). The mixture was stirred at room temperature for 18 hours, thenwater was added. The mixture was extracted twice with ethyl acetate andthe combined organic layers were dried over MgSO₄ and evaporated overIsolute® Flash-NH₂ silica gel. Chromatography (column: Isolute®Flash-NH₂ from Separtis; eluent: heptane/ethyl acetate=25:75) yieldedthe title compound as a white solid, (1.15 g, 73%). MS (ISP): 239.0([M+H]⁺).

S10 5-Chloro-pyrimidine-2-carboxylic acid{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide

The title compound was obtained in analogy to example S3 using5-chloropyrimidine-2-carboxylic acid (CAS 38275-61-5) instead of4-chlorobenzoic acid in step c). White solid. MS (ISP): 348.3([{³⁷Cl}M+H]⁺), 346.1 ([{³⁵Cl}M+H]⁺).

S11N-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide

a)(S)-2,2-Dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylicacid tert-butyl ester

To a stirred solution of diisopropylamine (L81 ml) in THF (50 ml) cooledto −78° C. was added dropwise a solution of n-butyllithium in hexane(8.05 ml, 1.6 M). The cooling bath was removed and the reaction mixturewas allowed to warm up to 10° C. before being re-cooled to −78° C. Asolution of (4-nitro-benzyl)-phosphonic acid diethyl ester (2.71 g, CAS2609-49-6) in THF (60 ml) was then added dropwise and the reactionmixture stirred at −78° C. for 1 hour. A solution of(R)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester(2.50 g, CAS 95715-87-0) in THF (50 ml) was then added dropwise over 30min and the mixture was then allowed to warm to room temperature over 90min. The mixture was then diluted with ethyl acetate and acidified byaddition of 1 N aq. hydrochloric acid. The mixture was then washedsequentially with water and with saturated brine. The organic phase wasseparated and was dried over sodium sulphate and concentrated in vacuo.The reside was purified by column chromatography (SiO₂; gradient:heptane/EtOAc) to give(S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylicacid tert-butyl ester (2.21 g, 64%) as a yellow oil. MS (EI): 333([M-CH₃]⁺), 292 ([M-C₄H₈]⁺), 277 ([M−CH₃−C₄H₈]⁺), 57 ([C₄H₉]⁺).

b)(S)-4-[2-(4-Amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a stirred suspension of(S)-2,2-dimethyl-4-[(E)-2-(4-nitro-phenyl)-vinyl]-oxazolidine-3-carboxylicacid tert-butyl ester (2.08 g) in methanol (140 ml) were added ammoniumformate (5.66 g) and palladium on charcoal (0.51 g, 10 wt %) and themixture was heated at 60° C. for 90 min. The mixture was then cooled toroom temperature, filtered through celite and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂; gradient: heptane/EtOAc) to give(S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (1.58 g, 82%) as a yellow oil. MS (ISP): 321.4([M+H]⁺).

c)(S)-4-{2-[4-(4-Chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

To a stirred solution of(S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (20) in THF (4 ml) were added 4-chlorobenzoic acid(147 mg), N-methylmorpholine (0.27 ml) and TBTU (401 mg). The reactionmixture was heated to 50° C. and stirred for 16 h. The reaction mixturewas then concentrated in vacuo and the residue was purified by flashcolumn chromatography (SiO₂; gradient: EtOAc/heptane) to afford(S)-4-{2-[4-(4-chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester as a white solid (254 mg, 89%). MS (ISP): 478.3([{³⁷Cl}M+NH₄]⁺), 476.3 ([{³⁵Cl}M+NH₄]⁺), 405.4 ([{³⁷Cl}M+H−C₄H₈]⁺),403.2 ([{³⁵Cl}M÷H—C₄H₈]⁺).

d) N-[4-((S)-3-Amino-4-hydroxy-butyl)-phenyl]-4-chloro-benzamide

To a solution of(S)-4-{2-[4-(4-chloro-benzoylamino)-phenyl]-ethyl}-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester (438 mg) in acetonitrile (5 ml) were added water(4 ml) and trifluoroacetic acid (0.29 ml). The mixture was heated at 80°C. for 4.5 h. The mixture was then cooled to room temperature and pouredinto 1 M aq. NaOH and extracted twice with EtOAc/THF. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to affordN-[4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-4-chloro-benzamide (255 mg,84%) a white solid. MS (ISP): 321.2 ([{³⁷Cl}M+H]⁺), 319.2([{³⁵Cl}M+H]⁺).

e)N-{4-[2-((S)-2-Amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide

To a stirred suspension ofN-[4-((S)-3-Amino-4-hydroxy-butyl)-phenyl]-4-chloro-benzamide (250 mg)and sodium acetate (124 mg) in methanol (10 ml) was added dropwise asolution of cyanogen bromide (100 mg) in methanol (3 ml). The resultingpale yellow solution was then stirred at room temperature for 16 h. Thereaction mixture was poured into 1 N aq. NaOH and extracted twice withdichloromethane/THF. The combined organic layers were washed with sat.aq. NaCl, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude material was purified by flash chromatography (silica gel; eluant:0% to 100% EtOAc in heptane, then 0% to 30% MeOH in EtOAc) to affordN-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide(150 mg, 56%) as a white solid. MS (ISP): 346.1 ([{³⁷Cl}M+H]⁺), 344.2([{³⁵Cl}M+H]⁺).

S12 (R)-2-Chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamidehydrochloride

The title compound was obtained in analogy to example S4 using(R)-2-(4-bromo-phenyl)-morpholine instead of(S)-2-(4-bromo-phenyl)-morpholine in step b) and2-chloro-6-methylisonicotinic acid (CAS 25462-85-5) instead of6-(2,2,2-trifluoroethoxy)nicotinic acid in step e). Light yellow solid.MS (ISP): 334.1 ([{³⁷Cl}M+H]⁺), 332.1 ([{³⁵Cl}M+H]⁺).

S13(S)—N-(4-(Morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamidehydrochloride

a) (S)-2-(4-Bromophenyl)morpholine

The enantiomers of (RS)-2-(4-bromo-phenyl)-morpholine (2.27 g,CAS-1131220-82-0) were separated using chiral HPLC (column: ChiralpakIA, 8×32 cm; eluent: n-heptane/ethanol

(1:11) containing 0.1% DEA) affording:(S)-2-(4-Bromo-phenyl)-morpholine: collected from 7.6 min to 9.4 min.Yield 0.97 g (42.9%) with 97.4% ee(R)-2-(4-Bromo-phenyl)-morpholine: collected from 9.8 min to 13.9 minYield 0.99 g (43.6%) with 97.4% ee

b) (S)-tert-Butyl 2-(4-bromophenyl)morpholine-4-carboxylate

(S)-2-(4-Bromo-phenyl)-morpholine (36.3 g) and N,N-diisopropylethylamine(31.4 ml) in THF (360 ml) were treated with di-tert-butyl dicarbonate(39.3 g). The reaction mixture was stirred for 17 h at room temperature,then concentrated in vacuo, diluted with ethyl acetate, washed with 1 Maq. citric acid (2×100 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude material was crystallized from hexaneto afford (S)-tert-butyl 2-(4-bromophenyl)morpholine-4-carboxylate (47.1g, 92%) as an off-white solid. MS (ISP): 344.1 ([M+H]⁺).

c) (S)-tert-Butyl2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate(S)-tert-Butyl

2-(4-bromophenyl)morpholine-4-carboxylate (47 g), diphenylmethanimine(29.9 g), BINAP (6.41 g) and Pd₂(dba)₃ (3.14 g) were dissolved underArgon in dry and de-aerated toluene (940 ml) and treated with sodiumtert-butoxide (18.5 g). The dark brown mixture was stirred at 90° C. for18 h. The yellow/brown reaction mixture was diluted with toluene (700ml), cooled to room temperature and extracted twice with water. Theorganic layer was separated, dried over magnesium sulfate andconcentrated in vacuo. The crude product was diluted with 300 ml hexane,stirred for 1 h and filtered off, leading to an orange solid (68 g)which was purified by column chromatography (silicagel, 20%ethylacetate/heptane). The combined and concentrated fractions weresuspended in hexane, stirred for 17 h, filtered off and dried in vacuoto yield (S)-tert-butyl2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (54.1 g,89%) as a yellow solid. MS (ISP): 443.3 ([M+H]⁺).

d) (S)-tert-Butyl 2-(4-aminophenyl)morpholine-4-carboxylate

A suspension of (S)-tert-Butyl2-(4-(diphenylmethyleneamino)phenyl)morpholine-4-carboxylate (54.1 g),ammonium formate (116 g) and 5% palladium on charcoal (6.5 g) inmethanol (930 ml) was stirred at 60° C. for 2 h. The reaction mixturewas filtered and concentrated in vacuo. The residue was dissolved inethyl acetate and water. The organic phase was extracted twice with 0.5M aq. HCl. The combined aqueous phases were basified with 2 M aq. NaOHand extracted twice with dichloromethane. The organic phases were driedover magnesium sulfate, filtered and dried in vacuo to yield(S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (31.95 g, 94%)as an off-white solid. MS (ISP): 279.1 ([M+H]⁺).

e) (S)-tert-Butyl2-(4-(6-(2,2,2-trifluoroethoxy)nicotinamido)phenyl)morpholine-4-carboxylate

To a stirred suspension of (S)-tert-butyl2-(4-aminophenyl)morpholine-4-carboxylate (1.5 g) in THF (75 ml) wereadded sequentially N-methylmorpholine (1.78 ml), HBTU (3.07 g) and6-(2,2,2-trifluoroethoxy)nicotinic acid (1.63 g) and the mixture wasstirred at room temperature for 17 h. The suspension was diluted withEtOAc and washed sequentially with 0.5 M aq. sat. aq. NaHCO₃ andsaturated brine. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The crude product was purified byrecrystallisation from heptane/EtOAc (1:1) to give (S)-tert-butyl2-(4-(6-(2,2,2-trifluoroethoxy)nicotinamido)phenyl)morpholine-4-carboxylate(2.11 g, 81%) as a white solid. MS (ISP): 482.1 ([M+H]⁺).

f)(S)—N-(4-(Morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamidehydrochloride

To a stirred suspension of (S)-tert-butyl2-(4-(6-(2,2,2-trifluoroethoxy)nicotinamido)phenyl)morpholine-4-carboxylate (2.11 g) in dioxane (8 ml)was added dropwise a solution of hydrogen chloride in dioxane (16.7 ml,4 M solution) and the mixture was heated at 60° C. for 2 hours. Thereaction mixture was cooled to room temperature, diluted with dioxane,and the crystalline product was collected by filtration, washing withEt₂O. The product was dried in vacuo to afford(S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamidehydrochloride (1.75 g, 94%) as a light yellow solid. MS (ISP): 382.2([M+H]⁺).

S14 (S)—N-(4-(Morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamidehydrochloride

The title compound was obtained in analogy to example S4 using2-(trifluoromethyl)isonicotinic acid (CAS 131747-41-6) instead of6-(2,2,2-trifluoroethoxy)nicotinic acid in step e). Off-white solid. MS(ISP): 352.3 ([M+H]⁺).

S15 (S)-1-(4-Fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)ureahydrochloride

a) (S)-tert-Butyl2-(4-(3-(4-fluorobenzyl)ureido)phenyl)morpholine-4-carboxylate

To a stirred solution of (S)-tert-butyl2-(4-aminophenyl)morpholine-4-carboxylate (100 mg) in DMF (3.5 ml) wereadded sequentially triethylamine (62 μl) and1-fluoro-4-(isocyanatomethyl)benzene (58.4 μl) and the mixture wasstirred at 60° C. for 17 h. The suspension was cooled to roomtemperature, then diluted with water and extracted twice with EtOAc. Thecombined organic phases were washed sequentially with water andsaturated brine. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified was purified by flashchromatography (silica gel; gradient: EtOAc/heptane) to afford(S)-tert-butyl2-(4-(3-(4-fluorobenzyl)ureido)phenyl)morpholine-4-carboxylate (164 mg,quant.) as a white solid. MS (ISP): 374.0 ([M+H−C₄H₈]⁺).

b) (S)-1-(4-Fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea hydrochloride

To a stirred suspension of (S)-tert-butyl2-(4-(3-(4-fluorobenzyl)ureido)phenyl) morpholine-4-carboxylate (163 mg)in THF (9 ml) was added dropwise a solution of hydrogen chloride indioxane (1.42 ml, 4 M solution) and the mixture was heated at 60° C. for6 hours. The reaction mixture was cooled to room temperature, dilutedwith EtOAc, and the crystalline product was collected by filtration,washing with Et₂O. The product was dried in vacuo to afford(S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea hydrochloride(101 mg, 73%) as a white solid. MS (ISP): 330.1 ([M+H]⁺).

S16 (S)-1-(3-Cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea hydrochloride

The title compound was obtained in analogy to example S7 using3-isocyanatobenzonitrile (CAS 16413-26-6) instead of1-fluoro-4-(isocyanatomethyl)benzene in step a). Off-white solid. MS(ISP): MS (ISP): 323.2 ([M+H]⁺).

S17 (S)-6-Chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide hydrochloride

The title compound was obtained in analogy to example S4 using6-chloronicotinic acid (CAS 5326-23-8) instead of6-(2,2,2-trifluoroethoxy)nicotinic acid in step e). Off-white solid. MS(ISP): MS (ISP): 320.1 ([{³⁷Cl}M+H]⁺), 318.1 ([{³⁵Cl}M+H]⁺).

In Vitro Functional Activity of TAAR1 Agonists at Mouse TAAR1 Receptor

Recombinant HEK293 cells expressing the mouse TAAR1 were grown at 37° C.and 5% CO2/95% air in 250 ml Falcon culture flasks in 30 ml culturemedium. The cell culture medium contained DMEM high glucose, fetal calfserum (10%, heat inactivated for 30 min at 56° C.), geneticin G418 (500μg/ml), and penicillin/streptomycin (1%). Cells were harvested when80-90% confluent. Then culture medium was then removed from the cultureflasks, cells washed once with 5 ml of PBS. After removing the washsolution, 5 ml of trypsin/EDTA solution were added for 5 min at 37° C.Afterwards, 45 ml of culture medium was added to the 5 ml detached cellsolution and the total 50 ml transferred into a 50 ml Falcon tube (ref:2070), the tube was centrifuged at 1300 rpm for 3 min at RT and theculture medium removed. The cell pellet was resuspended in fresh culturemedium and brought to 5×10 E5 cells per milliliter. Then the cells wereplated in 96-well Plate (BIOCOAT 6640 from Becton Dickinson) with amultipipette (100 μl/well, 50 000 cells/well) and incubated 20 h at 37°C.

cAMP Assay:

The cell culture medium was removed and the cells washed once with PBS.50 μl of PBS (AMIMED Endotoxine free: 8-05F00-1) with 1 mM IBMX wereadded and the cells allowed to incubate for 30 min at 37° C. and 5%CO2/95% air. Then 50 μl of a (e.g.) 20 μM compound solution or 50 μl ofa 50% beta-PEA stimulation concentration in PBS (AMIMED Endotoxine free)with 1 mM IBMX were added and the cells incubated for 30 min at 37° C.as above again. After the incubation the cells were lysed with 50 μl ofthe 3× Detection Mix solution containing Ru-cAMP, Alexa700-cAMP Ab andlysis buffer for at least 60 min (better 2 h) at RT under strongshaking. The fluorescence is measured on the NanoScan (10M reader) (Ex.456 nm, Em. 630 & 700 nm).

The compounds show an EC₅₀ value (μM) at mouse TAAR1 in the range of<0.01 μM as shown in the table below. Efficacy values (% eff.) arerelative to phenylethylamine having 100% agonistic activity.

EC₅₀ (μM) Example % efficacy S1 0.0020 90% S2 0.0018 65% S3 0.0013 67%S4 0.0033 65% S5 0.0016 51% S6 0.0014 78% S7 0.0008 57% S8 0.0074 65% S90.0017 99% S10 0.0016 32% S11 0.0001 45% S12 0.0031 69% S13 0.0016 54%S14 0.0046 55% S15 0.0006 40% S16 0.0004 60% S17 0.0018 39%

Antipsychotic-Like Activity of TAAR1 Agonists Additive and Synergisticto the Marketed Antipsychotic Olanzapine in Two Animal Models Indicativefor Psychosis Additive Effect of TAAR1 Agonists and Olanzapine inCocaine-Induced Locomotion Test in Mice

Activation of TAAR1 was shown to down-modulate dopaminergicneurotransmission, whereas inhibition of TAAR1 was shown to enhance it(Lindemann et al., 2008; Bradaia et al., 2009). Data from cocaine- andL-687414 (benzyloxyamine)-induced hyperlocomotor activity tests in miceindicate that TAAR1 agonists have potential antipsychotic-like activity.

At doses that had modest effects on baseline locomotor activity, S2significantly antagonized cocaine-induced hyperlocomotor activity at 1and 3 mg/kg p.o. in mice. In addition, partially active doses of S2 (0.3mg/kg, p.o.) and olanzapine (0.3 mg/kg, p.o.), when combined, fullyreversed the hyperlocomotion induced by cocaine (FIG. 1 a). Thisindicates that S2 may have an additive effect on the marketedantipsychotic olanzapine.

It was also observed that, while doses of S1 (0.1 mg/kg, p.o.) andolanzapine (0.3 mg/kg, p.o.) partially antagonized cocaine-inducedlocomotor activity when tested separately, a full reversal ofcocaine-induced hyperlocomotor activity was observed when thesecompounds were combined (FIG. 1 b).

This indicates that S1 has an additive effect on the marketedantipsychotic olanzapine, supporting its potential as add-on therapy tomarketed antipsychotics.

FIG. 1 Effects on Cocaine-Induced Locomotion in Mice

FIG. 1A Doses of S1 (0.1 mg/kg p.o.) and olanzapine (0.3 mg/kg p.o.),that partially antagonized cocaine-induced hyperlocomotor activity whentested alone, showed a normalization effect when combined. *p≦0.05,**p≦0.01, ***p≦0.002 versus “vehicle and cocaine” group.

FIG. 1B Doses of S2 (0.3 mg/kg p.o.) and olanzapine (0.3 mg/kg p.o.),that partially antagonized cocaine-induced hyperlocomotor activity whentested alone, showed a normalization effect when combined. *p≦0.05,**p≦0.01, ***p≦0.002 versus “vehicle and cocaine” group.

Synergistic Effect of TAAR1 Agonist and Olanzapine in L-687414-InducedLocomotion Test in Mice

To address its potential effect on the glutamatergic system, S2(0.00003—1 mg/kg, p.o.) was tested in the acute procedure of L-687414(N-hydroxy-3-amino-4-methyl-pyrrolidin-2-one, NMDA receptor antagonistacting at the glycine site)-induced hyperlocomotion in mice, where itdose-dependently antagonized L-687414, with significance in the doserange of 0.003 to 1 mg/kg, p.o. (FIG. 2).

FIG. 2

Effects of TAAR1 Agonist on L-687414-Induced Locomotion in Mice

L-687414-Induced Locomotion: S2 (0.00003—1 mg/kg p.o.) fully antagonizedL-687414-induced hyperlocomotor activity from 0.003 to 1 mg/kg (filledcircles). *p≦0.05, **p≦0.01, ***p≦0.001 versus vehicle (empty circles).

Furtheron, a partially active dose of the TAAR1 agonist S2 (0.001 mg/kg,p.o.; grey bar in FIG. 2) was added to increasing doses of olanzapine(0-0.1 mg/kg, p.o.). As shown in FIG. 3, partially active dose of S2(0.001 mg/kg, p.o.) combined with non-active doses of olazapine(0.02-0.06 mg/kg, p.o.) fully antagonized L-687414-induced locomotoractivity, indicating that the TAAR1 agonist and olanzapine showsynergistic effects in this mouse model indicative for schizophrenia.

FIG. 3 Synergism with Olanzapine in L-687414-Induced Locomotion in Mice

L-687414-Induced Locomotion: S2 (0.001 mg/kg, p.o.) combined withincreasing doses of olazapine (0-0.1 mg/kg, p.o.) fully antagonizedL-687414-induced hyperlocomotor activity at 0.02 and 0.06 mg/kgolazapine. *p≦0.05, **p 0.01, ***p≦0.001 L-687414+S2 vs L-687414 groupalone.

Acute Effect of TAAR1 Agonists on Oral Glucose Tolerance Test (oGTT) inRegular Male C57Bl6 Mice

An oral glucose tolerance test (oGTT) was performed in C57Bl6 mice toaddress potential anti-diabetic effects of TAAR1 agonists. Male C57BL/6Jmice (Charles River Laboratories, Lyon, France) were stratified intogroups of 8 mice according to body weight. The evening before theanimals received 1 g food, this corresponds to a fasting period of about10 hours. At the experiment day the animals were treated with TAAR1agonists or placebo (0.3% Tween 80) 45 minutes prior to an oral glucosechallenge of 2 g/kg. The main readout was blood glucose measured withAccu-Chek Aviva. In parallel blood samples were taken for insulindetermination.

S1 significantly lowered blood glucose excursion at 0.1 and 0.3 mg/kg,p.o. compared to vehicle after glucose challenge (FIG. 4A). At the sametime, insulin excursion was significantly lower upon TAAR1 agonistadministration compared to vehicle treatment (FIG. 4B). No effect onfasting glucose levels were observed using S1. As metabolic syndrome hasa high prevalence in schizophrenia, an anti-diabetic effect isenvisioned to have a positive impact on schizophrenic patients.

FIG. 4 Effect of S1 on Glucose and Insulin AUC in oGTT in Mice

S1 (0.1, 0.3 mg/kg p.o.) markedly lowered FIG. 4A glucose and FIG. 4Binsulin AUC (0-60 min) during oGTT in mice. Results are shown asmean±SEM. Statistics: Anova followed by Dunett's post hoc test,**p≦0.01, ***p≦0.001 versus vehicle (Veh) group; n=8/group.

Several additional TAAR1 agonists (S2-8) with various levels of efficacy(51-90% compared to beta-phenylethylamine) were tested in the oGTT andall showed a significant effect in reducing glucose AUC and whereastested in reducing insulin AUC (FIG. 5-9)

FIG. 5 Effect of S2 on Glucose and Insulin AUC in oGTT in Mice

S2 (0.3, 1 mg/kg, p.o.) markedly lowered (a) glucose and (b) insulin AUC(0-60 min) during oGTT in mice. Results are shown as mean±SEM.Statistics: Anova followed by Dunett's post hoc test, ***p≦0.001 versusvehicle (Veh) group; n=8/group.

FIG. 6 Effect of S3 on Glucose and Insulin AUC in oGTT in Mice

S3 (1, 3 mg/kg p.o.) markedly lowered (a) glucose and (b) insulin AUC(0-60 min) during oGTT in mice. Results are shown as mean±SEM.Statistics: Anova followed by Dunett's post hoc test, *p≦0.05,***p≦0.001 versus vehicle (Veh) group; n=8/group.

FIG. 7 Effect of S4 on Glucose and Insulin AUC in oGTT in Mice

S4 (03 mg/kg, p.o.) markedly lowered (a) glucose and (b) insulin AUC(0-60 min) during oGTT in mice. Results are shown as mean±SEM.Statistics: Anova followed by Dunett's post hoc test, *p≦0.05,***p≦0.001 versus vehicle (Veh) group; n=8/group.

FIG. 8 Effect of S5 on Glucose AUC in oGTT in Mice

S5 (30 mg/kg, p.o.) markedly lowered glucose AUC (0-60 min) during oGTTin mice. Results are shown as mean±SEM. Statistics: Anova followed byDunett's post hoc test, ***p 0.001 versus vehicle group; n=8/group.

FIG. 9 Effects of S6, S7 and S8 (10 mg/kg, p.o., each) on Glucose AUC inoGTT in Mice

S6 (10 and 30 mg/kg, p.o.), S7 (10 mg/kg, p.a.), and S8 (10 and 30mg/kg, p.o.) markedly lowered glucose AUC (0-60 min) during oGTT inmice. Results are shown as mean±SEM. Statistics: Anova followed byDunett's post hoc test, **p≦0.01, ***p≦0.001 versus vehicle group;n=8/group.

FIG. 10 Effects of S9, S10 and S11 on Glucose AUC in oGTT in Mice

FIG. 10A S9 (10 mg/kg, p.o.) and S10 (10 mg/kg, p.o.) as well as FIG.10B S11 (1 and 3 mg/kg, p.o.) markedly lowered glucose AUC (0-60 min)during oGTT in mice. Results are shown as mean±SEM. Statistics: Anovafollowed by Dunett's post hoc test, *p≦0.05, **p≦0.01, ***p≦0.001 versusvehicle group; n=8/group.

FIG. 11 Effects of S12, S13, S14, S15 and S16 on Glucose AUC in oGTT inMice

FIG. 11A S12 and S13 (3 mg/kg, p.o., each) as well FIG. 11B S14, 515 andS16 (1 mg/kg, p.o., each) markedly lowered glucose AUC (0-60 min) duringoGTT in mice. Results are shown as mean±SEM. Statistics: Anova followedby Dunett's post hoc test, *p≦0.05, **p≦0.01, ***p≦0.001 versus vehiclegroup; n=8/group.

FIG. 12 Effects of S17 (0.3 and 1 mg/kg, p.o.) on Glucose AUC in oGTT inMice

S17 (0.3 and 1 mg/kg, p.o.) markedly lowered glucose AUC (0-60 min)during oGTT in mice. Results are shown as mean±SEM. Statistics: Anovafollowed by Dunett's post hoc test, **p≦0.01, ***p≦0.001 versus vehiclegroup; n=8/group.

TAAR1 Agonists Reduce Weight Gain Increase in Normal Rats and NormalizeWeight Gain Increase Induced by the Antipsychotic Drug Olanzapine

Many antipsychotic drugs induce weight gain in patients withschizophrenia. Since weight gain can lead to serious healthcomplications and diseases such as diabetes, it is crucial to evaluatepromising, newer antipsychotic compounds in animals for their propensityto alter weight.

A 14-day treatment regimen was used in female Sprague-Dawley rats withS2 and olanzapine, a clinically-used antipsychotic drug that is know toproduce weight gain. Along with body weight measurement, magneticresonance (MR) relaxometry was employed to determine, in a noninvasivemanner, fat mass composition in the animals.

The results show that S2 at 3 and 10 mg/kg p.o. reduced weight gain(FIG. 13A), fat mass (FIG. 14A, 14B) and food intake (Table 1) ascompared to vehicle-treated animals, without inducing weight loss whencompared to pre-treatment values. No significant effect was measured at1 mg/kg p.o. (FIG. 13B, 14B, Table 1). In addition, S2 (1 mg/kg p.o.)combined with olanzapine (2 mg/kg p.o.) reduced the increase in weightgain, fat mass content and food intake measured in olanzapine-treatedrats (FIG. 13B, 14B, Table 1).

This indicates that S2 does not induce weight gain when administeredalone, and can inhibit the weight gain induced by the marketedantipsychotic olanzapine.

FIG. 13 Effects of S2 on Cumulative Weight Gain in Rats

FIG. 13A S2 at 3 and 10 mg/kg, but not at 1 mg/kg p.o. reduced weightgain in female Sprague-Dawley rats (contrasts of linear trends in S2groups vs linear trend in vehicle group, p=0.0024 at 3 mg/kg and p=0.012at 10 mg/kg). FIG. 13B S2 (1 mg/kg p.o.) combined with olanzapine (2mg/kg p.o.) normalized the olanzapine-induced weight gain (linear trendsolanzapine vs vehicle, p=4.6E-10; S2/olanzapine vs vehicle, p=0.41).Between-group comparisons at each time point: t-test, *p≦0.05, **p≦0.01,***p≦0.001 versus vehicle; # p≦0.05, ## p≦0.01, ###p≦0.001 versusolanzapine group; n=8/group.

FIG. 14 Effects of S2 on Fat Mass Content in Rats

S2 (1 mg/kg p.o.) combined with olanzapine (2 mg/kg p.o.) normalized theolanzapine-induced fat mass increase in female Sprague-Dawley rats. Nosignificant effect of S2 alone was measured when compared to the vehiclegroup. Dunett's test *p≦0.05, **p≦0.01, ***p≦0.001 versus vehicle; #p≦0.05, ## p≦0.01, ### p≦0.001 versus olanzapine group; n=8/group asillustrated in FIG. 14C.

TABLE 1 Cumulative food Dunnett's test Treatment intake ± SEM (g) pvalue Study 1 Vehicle 254.9 ± 7.0 S2 (3 mg/kg) 233.8 ± 7.4 0.18 S2 (10mg/kg) 217.0 ± 7.3 0.0050 Study 2 Vehicle 263.4 ± 3.8 S2 (1 mg/kg) 248.8± 5.0 0.45 Olanzapine (2 mg/kg) 301.6 ± 8.6 0.0034 S2 (1 mg/kg) & 268.6± 8.6 0.96 Olanzapine (2 mg/kg)

Effects of S2 on Cumulative Food Intake in Rats

S2 (1 mg/kg p.o.) combined with olanzapine (2 mg/kg p.o.) normalized theolanzapine-induced increase in food intake. A significant reduction infood intake was measured in S2-treated rats at 10 mg/kg; n=8/group.

Olanzapine and the compounds of formulas I, I-1, II and II-1 and thepharmaceutically acceptable salts can be used as medicaments, e.g. inthe form of pharmaceutical compositions. The pharmaceutical compositionscan be administered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds of formulas I, I-1, II and II-1 can be processed withpharmaceutically inert, inorganic or organic carriers for the productionof pharmaceutical compositions. Lactose, corn starch, cellulose orderivatives thereof, talc, stearic acids or its salts and the like canbe used, for example, as such carriers for tablets, coated tablets,dragées and hard gelatin capsules. Suitable carriers for soft gelatincapsules are, for example, vegetable oils, waxes, fats, semi-solid andliquid polyols and the like. Depending on the nature of the activesubstance no carriers are however usually required in the case of softgelatin capsules. Suitable carriers for the production of solutions andsyrups are, for example, water, polyols, glycerol, vegetable oil and thelike. Suitable carriers for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The invention also provides pharmaceutical compositions containingolanzapine and a compound of formulas I, I-1, II and II-1 or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier, and provides a process for their production, which comprisesbringing one or more compounds of formulas I, I-1, II and II-1 andolanzapine and/or pharmaceutically acceptable acid addition salts and,if desired, one or more other therapeutically valuable substances into agalenical administration form together with one or more therapeuticallyinert carriers.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg per day of olanzapine and a compound of general formulasI, I-1, II and II-1 or of the corresponding amount of a pharmaceuticallyacceptable salt thereof. The daily dosage can be administered as singledose or in divided doses and, in addition, the upper limit can also beexceeded when this is found to be indicated.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. LactoseAnhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. MicrocrystallineCellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148— 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 12 2 5 Total 200 200 300 600

Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add items 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

Olanzapine Tablet Formulation mg/capsule Item Ingredients 2.5 mg 7.5 mg15 mg 20 mg 1. Olanzapine 2.5 7.5 15.0 20.0 2. Lactose monohydrate 89.084.0 76.5 71.5 3. Hyprolose 7.5 7.5 7.5 7.5 4. Crospovidon 4.5 4.5 4.54.5 5. Macrocrystalline Cellulose 45.0 45.0 45.0 45.0 6.Magnesiumstearate 1.5 1.5 1.5 1.5 Total 150.0 150.0 150.0 150.0

Manufacturing Procedure

1. Mix items 1 to 5 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add item 6 and mix for three minutes; compress on a suitable press.

Combination formulation Item Ingredients mg/capsule Compound of formulaI/ 5/2.5 25/2.5 100/15 mg Olanzapine 1. Compound of formula I 5.00 25.00100.00 2. Olanzapine 2.50 2.50 15.00 3. Lactose monohydrate 166.25146.25 58.75 4. Povidon K30 12.50 12.50 12.50 5. Croscarmellose Sodium7.50 7.50 7.50 6. Microcrystalline Cellulose 50.00 50.00 50.00 7.Magnesiumstearate 1.25 1.25 1.25 8. Talc 5.00 5.00 5.00 Total 250.00250.00 250.00

Manufacturing Procedure

1. Mix items 1 to 6 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add item 7 and 8 and mix for three minutes; compress on a suitablepress.

1. (canceled)
 2. A combination comprising a therapeutically effectiveamount of each of olanzapine and a TAAR1 agonist I comprising a compoundof formula II

wherein R is hydrogen or lower alkyl; R¹ is—(CH₂)_(n)—(O)_(o)-heterocycloalkyl, optionally substituted by loweralkyl, hydroxy, halogen, or by —(CH₂)_(p)-aryl; n is 0, 1 or 2; o is 0or 1; p is 0, 1 or 2; R² is cycloalkyl, heterocycloalkyl, or is aryl orheteroaryl, wherein the aromatic rings are optionally substituted by oneor two substituents, selected from lower alkyl, halogen, heteroaryl,CF₃, OCF₃, OCH₂CF₃, lower alkoxy, CH₂-lower alkoxy, lower alkynyl orcyano; X is a bond, —NR′—, —CH₂NH—, —CHR″—, —(CH₂)_(q)—O— or —(CH₂)₂—;R′ is hydrogen or lower alkyl, R″ is hydrogen, lower alkyl, loweralkoxy, and q is 0, 1 or 2; or a pharmaceutically suitable acid additionsalt thereof.
 3. (canceled)
 4. The combination of claim 2, comprisingolanzapine and a TAAR1 agonist selected from the group consisting of5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide;4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide; and1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea.
 5. Thecombination of claim 2, comprising olanzapine and a TAAR1 agonistselected from the group consisting of 5-chloro-pyrimidine-2-carboxylicacid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;(R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;(S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;(S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;(S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;(S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; and(S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.
 6. (canceled) 7.A method for treating schizophrenia and manic episodes associated withbipolar disorders with reduced incidence of metabolic syndrome,comprising administering to a human in need thereof an effective amountof a combination comprising a therapeutically effective amount of eachof olanzapine and a TAAR1 agonist comprising a compound of formula II

wherein R is hydrogen or lower alkyl; R¹ is—(CH₂)_(n)—(O)_(o)-heterocycloalkyl, optionally substituted by loweralkyl, hydroxy, halogen, or by —(CH₂)_(p)-aryl; n is 0, 1 or 2; o is 0or 1; p is 0, 1 or 2; R² is cycloalkyl, heterocycloalkyl, or is aryl orheteroaryl, wherein the aromatic rings are optionally substituted by oneor two substituents, selected from lower alkyl, halogen, heteroaryl,CF₃, OCF₃, OCH₂CF₃, lower alkoxy, CH₂-lower alkoxy, lower alkynyl orcyano; X is a bond, —NR′—, —CH₂NH—, —CHR″—, —(CH₂)_(q)—O— or —(CH₂)₂—;R′ is hydrogen or lower alkyl, R″ is hydrogen, lower alkyl, loweralkoxy, and q is 0, 1 or 2; or a pharmaceutically suitable acid additionsalt thereof.
 8. The method of claim 7, wherein the reduced incidence ofmetabolic syndrome results from antidiabetic efficacy with loweringblood glucose excursion fat mass and body weight.
 9. (canceled) 10.(canceled)
 11. The method of claim 7, wherein the TAAR1 agonist isselected from the group consisting of 5-chloro-pyridine-2-carboxylicacid (4-pyrrolidin-3-yl-phenyl)-amide;4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide; and1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea.
 12. Themethod of claim 7, wherein the TAAR1 agonist is selected from the groupconsisting of 5-chloro-pyrimidine-2-carboxylic acid{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;(R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;(S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;(S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;(S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;(S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; and(S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.
 13. Apharmaceutical composition comprising a combination of olanzapine and aTAAR1 agonist comprising a compound of formula II

wherein R is hydrogen or lower alkyl; R¹ is—(CH₂)_(n)—(O)_(o)-heterocycloalkyl, optionally substituted by loweralkyl, hydroxy, halogen, or by —(CH₂)_(p)-aryl; n is 0, 1 or 2; o is 0or 1; p is 0, 1 or 2; R² is cycloalkyl, heterocycloalkyl, or is aryl orheteroaryl, wherein the aromatic rings are optionally substituted by oneor two substituents, selected from lower alkyl, halogen, heteroaryl,CF₃, OCF₃, OCH₂CF₃, lower alkoxy, CH₂-lower alkoxy, lower alkynyl orcyano; X is a bond, —NR′—, —CH₂NH—, —CHR″—, —(CH₂)_(q)—O— or —(CH₂)₂—;R′ is hydrogen or lower alkyl, R″ is hydrogen, lower alkyl, loweralkoxy, and q is 0, 1 or 2; or a pharmaceutically suitable acid additionsalt thereof and one or more pharmaceutically acceptable excipients. 14.(canceled)
 15. (canceled)
 16. The pharmaceutical composition of claim13, wherein the TAAR1 agonist is selected from the group consisting of5-chloro-pyridine-2-carboxylic acid (4-pyrrolidin-3-yl-phenyl)-amide;4-chloro-N-(4-pyrrolidin-3-yl-phenyl)-benzamide; and1-(5-chloro-pyridin-2-yl)-3-(4-pyrrolidin-3-yl-phenyl)urea.
 17. Thepharmaceutical composition of claim 13, wherein the TAAR1 agonist isselected from the group consisting of 5-chloro-pyrimidine-2-carboxylicacid {4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-amide;N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-benzamide;(R)-2-chloro-6-methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide;(S)—N-(4-(morpholin-2-yl)phenyl)-6-(2,2,2-trifluoroethoxy)nicotinamide;(S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide;(S)-1-(4-fluorobenzyl)-3-(4-(morpholin-2-yl)phenyl)urea;(S)-1-(3-cyanophenyl)-3-(4-(morpholin-2-yl)phenyl)urea; and(S)-6-chloro-N-(4-(morpholin-2-yl)phenyl)nicotinamide.
 18. A compound ofclaim 5, which is(S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide. 19.The method of claim 12, wherein the TAAR1 agonist is(S)—N-(4-(morpholin-2-yl)phenyl)-2-(trifluoromethyl)isonicotinamide. 20.The pharmaceutical composition of claim 17, wherein the TAAR1 agonist is(S)—N-(4-(morpholin-2-ylphenyl)-2-(trifluoromethyl)isonicotinamide.